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BCR (Breakpoint cluster region)

Identity

Other namesBCR1
PHL (Philadelphie)
HGNC (Hugo) BCR
LocusID (NCBI) 613
Location 22q11.23
Location_base_pair Starts at 23522552 and ends at 23660224 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Distal to IGL in 22q11.1, proximal to EWS and NF2, both in 22q12.
 
  Map of the BCR region; - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

DNA/RNA

 
  DNA Diagram
Description About 23 exons; 130 kb; 5' centromere - 3' telomere orientation.
Transcription Into various mRNA, of which are 4.5 kb and 7 kb.

Protein

Description 130 KDa, 190 KDa; mainly 160 KDa (1271 amino acids); N-term ATP binding/Serine-Threonine kinase domain, SH2 binding, GTP/GDP exchange domain, and C-term domain which functions as a GTPase activating protein for p21rac.
Expression Ubiquitously expressed, with highest expression in brain and hematopoietic tissue.
Localisation Cytoplasmic.
Function Protein (serine/threonine) kinase; includes major signalisation domains such as:
  • Oligomerization domain, responsible of homotetramerization of BCR-ABL molecule and necessary for its transforming potential;
  • Serine threonine kinase domain, including at least three SH2 binding sites; able to interact with proteins with SH2 domains: These sites include TYR177, necessary for binding of Grb2 and activation of RAS pathway and beta-isoform of 14-3-3 proteins;
  • GEF domain, in which lie the binding activity to the xeroderma pigmentosum protein, involved in DNA repair;
  • A COOH-terminal RAC-GAP domain which does not participate to hybrid BCR-ABL proteins.
    From the functional point of view, the role of bcr has been studies in bcr-null mice which shows an increased respiratory burst suggesting the involvement of bcr protein in the regulation of superoxide production , probably via RAC.
    In the context of CML, the role of bcr protein has been studies in in vitro and in vivo models; bcr gene has been shown to be a negative regulator of BCR-ABL. Its reduced expression increases the transforming potential of BCR-ABL. When overexpressed, bcr blocks BCR-ABL-mediated transformation in experimental mouse models. Serine 354 is required for the inhibitory function of bcr over BCR-ABL, as kinase mutants of bcr overexpressed in BCR-ABL expressing cells induce an increased tumorigenicity.
  • Homology Drosophila rotund protein; other guanine-nucleotide releasing factors of the CDC24 family.

    Implicated in

    Entity t(9;22)(q34;q11)/chronic myelogenous leukemia (CML) --> BCR / ABL
    Disease All CML have a t(9;22), at least at the molecular level (BCR/ABL); phenotype and stem cell origin: multipotent progenitor: t(9;22) is found in all myeloid and B- lineage progenitors.
    Prognosis The prognosis of CML has changed radically over the last 10 years, due to the development of novel drugs able to target the enhanced tyrosine kinase activity of BCR-ABL. The first of these therapies is Imatinib Mesylate (Gleevec) which has become the first line therapy for all patients with CML (See ABL and CML). In the first cohort trial of patients treated with Imatinib mesylate, the rates of complete cytogenetics responses (CCR) were exceptionally high (82 %) as compared to standard IFN-alpha - ARA-C therapy. At the most recent 6-year update, the overall survival is 90 % and most interestingly, the rates of progression towards more aggressive phases have been found to be progressively decreasing in all patients with major molecular responses (MMR). (For definition of MMR see CML). In IM-resistant or relapsing Ph1+ CML patients, second generation tyrosine kinase inhibitor (TKI) therapies such as Dasatinib (a dual SRC and ABL inhibitor) and Nilotinib have also recently become available.
    Cytogenetics Anomalies additional to the t(9;22) may be found either at diagnosis or during course of the disease, or at the time of acute transformation; mainly: +der(22), +8, i(17q), +19; +21, -Y, -7, -17,+17; variant translocations: t(9;22;V) and apparent t(V;22) or t(9;V), where V is a variable chromosome, karyotypes with apparently normal chromosomes 9 and 22, may be found.
    Deletion of the derivative chromosome 9: Detected at diagnosis (in 10% of patients), probably indiacting a genetic instability phenotype, this finding has been associated to the more aggressive behavior of the disease, a poor prognostic factor potentially reversed by the use of imatinib mesylate.
     
    72M14 on a case of CML with t(9/22). Note that the probe remains on der(22) (Ph) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics .
    Hybrid/Mutated Gene see below
    Abnormal Protein see below
    Oncogenesis see below
      
    Entity t(9;22)(q34;q11)/acute lymphoblastic leuke¨ia (ALL) --> BCR / ABL
    Disease Most often CD 10+ B-ALL; frequent CNS involvement.
    Prognosis The prognosis of Ph1+ ALL has changed since the introduction of tyrosine-kinase inhibitor therapies, especially imatinib mesylate which is currently used as a first line therapy associated with either high dose chemotherapy or classical ALL-type induction (steroids+ vincristine) and maintenance. Allogeneic stem cell transplantation is indicated in Ph1+ ALL patients relapsing after Imatinib-based regimens. In IM-resistant or relapsing Ph1+ ALL patients, second generation tyrosine kinase inhibitor (TKI) therapies such as Dasatinib (a dual SRC and ABL inhibitor) and Nilotinib have also recently become available.
    Cytogenetics The chromosome anomaly t(9;22) disappear during remission, in contrast with BC-CML cases (CML in blast crisis); additional anomalies: +der(22), -7, del(7q) most often, +8, but not an i(17q), in contrast with CML and AML cases; complex karyotypes, often hyperploid; variants and complex translocations may be found as in CML.
    Hybrid/Mutated Gene see below. In Both CML and Ph1+ ALL, detection and quantification of p210 BCR-ABL and p190 BCR-ABL have become the cornerstones of monitoring targeted therapies.
    Abnormal Protein see below
    Oncogenesis see below
      
    Entity t(9;22)(q34;q11)/acute myeloid leukemia (AML) --> BCR / ABL
    Disease AML mostly M1 or M2 AML
    Prognosis High rates of hematologic , cytogenetic and molecular responses have been reported in de novo PH1+ AML, which is a rare entity.
    Cytogenetics The chromosome anomaly t(9;22) disappear during remission, in contrast with BC-CML cases (CML in blast crisis); additional anomalies: similar to what is found in CML.
    Hybrid/Mutated Gene BCR/ABL the crucial event lies on der(22), id est 5' BCR - 3' ABL hybrid gene is the crucial one, while ABL/BCR may or may not be expressed;
    Breakpoint in ABL is variable over a region of 200 kb, often between the two alternative exons 1b and 1a, sometimes 5' of 1b or 3' of 1a, but always 5' of exon 2; breakpoint in BCR is either:
  • 1- in a region called M-bcr (for major breakpoint cluster region), a cluster of 5.8 kb, between exons 12 and 16, also called b1 to b5 of M-bcr; most breakpoints being either between b2 and b3, or between b3 and b4; transcript is 8.5 kb long; this results in a 210 KDa chimeric protein (P210); this is found in (most cases of) CML, and in half cases of ALL or AML.
  • 2- in a 35 kb region between exons 1 and 2, called m-bcr (minor breakpoint cluster region), -> 7 kb mRNA, resulting in a 190 KDa protein (P190) found in approximately 25% of adult ALL cases.
  • 3- A breakpoint in the exon 19 of BCR (designed as the micro-bcr) with fusion to abl sequences (a2) has been found in neutrophilic CML, with presence of a larger protein (P230).
  • Abnormal Protein BCR/ABL P210 comprises the first 902 or 927 amino acids from N-term of BCR, whereas P190 BCR and P230 include 427 and 1176 aminoacids respectively, from the N-term region of BCR; BCR/ABL has a cytoplasmic localization, probably by the ability of the oligomerization domain to interact with Factin. ABL is both nuclear and cytoplasmic, due to the presence of nuclear localisation and export signals (NLS and NES) within its COOH terminal region.
    Oncogenesis All three forms of BCR-ABL oncogenes have transforming potential and it is now clear that they are responsible for initiation of the leukemic process associated with BCR-ABL oncogenes: Several signalling pathways are simultaneously activated and some phenotypic correlations can be made with the molecular abnormalities
  • 1- Constitutive activation of RAS pathway (via TYR177 of the BCR) mimicking the growth-factor-stimulation of cells, leads to a proliferative behavior;
  • 2- Activation of PI-3K/Akt as well as JAK/STAT pathways is most likely responsible for the anti-apoptotic potential;
  • 3- BCR/ABL provokes cell adhesive abnormalities (via CRK-L, FAK) as well as abnormalities of cell migration (via CXCR-4 whose expression is downregulated in CML cells expressing high levels of BCR-ABL). In experimental settings CD44 has been shown to play a major role in homing of BCR-ABL expressing cells. Activation of focal adhesion molecules (FAK / ) via CRK-L as well as abnormal response to SDF-1 leads to adhesive and migratory abnormalities of leukemic cells. It should be noted that specific signalling events leading to ALL with P190 and to CML with P210 have not been clearly established. A differential activation of Rho protein could play a role between the two phenotypes: rho Rac and cdc42 interact with BCR-ABL p210 but BCR-ABL p190 activates rac and cdc42 only. Deletion of Ikaros, has recently been implicated as a major oncogenic event cooperating with BCR-ABL in the BCR-ABL+ ALL.
  • Progression to blast crisis in CML: Multiple events could be involved, with the major phenotype being a genetic instability: 1-Mutation of P53, 2-methylation of internal ABL promoter; 3- telomere shortening; 4- Inhibition of negative regulators of BCR-ABL (such as Abi-1) 5- BCR-ABL induces a major genetic instability: Molecular pathways involved in this phenomenon have recently been elucidated (See ABL AND CML).
  •   

    Breakpoints

     

    External links

    Nomenclature
    HGNC (Hugo)BCR   1014
    Cards
    AtlasBCR
    Entrez_Gene (NCBI)BCR  613  breakpoint cluster region
    GeneCards (Weizmann)BCR
    Ensembl (Hinxton)ENSG00000186716 [Gene_View]  chr22:23522552-23660224 [Contig_View]  BCR [Vega]
    AceView (NCBI)BCR
    Genatlas (Paris)BCR
    WikiGenes613
    SOURCE (Princeton)NM_004327 NM_021574
    Genomic and cartography
    GoldenPath (UCSC)BCR  -  22q11.23   chr22:23522552-23660224 +  22q11   [Description]    (hg19-Feb_2009)
    EnsemblBCR - 22q11 [CytoView]
    Mapping of homologs : NCBIBCR [Mapview]
    OMIM151410   608232   613065   
    Gene and transcription
    Genbank (Entrez)AB209991 AB742170 AB742171 AF192533 AF487522
    RefSeq transcript (Entrez)NM_004327 NM_021574
    RefSeq genomic (Entrez)AC_000154 NC_000022 NC_018933 NG_009244 NT_011520 NW_001838745 NW_004929430
    Consensus coding sequences : CCDS (NCBI)BCR
    Cluster EST : UnigeneHs.715409 [ NCBI ]
    CGAP (NCI)Hs.715409
    Alternative Splicing : Fast-db (Paris)GSHG0019873
    Alternative Splicing GalleryENSG00000186716
    Gene ExpressionBCR [ NCBI-GEO ]     BCR [ SEEK ]   BCR [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP11274 (Uniprot)
    NextProtP11274  [Medical]
    With graphics : InterProP11274
    Splice isoforms : SwissVarP11274 (Swissvar)
    Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
    Domaine pattern : Prosite (Expaxy)C2 (PS50004)    DH_1 (PS00741)    DH_2 (PS50010)    PH_DOMAIN (PS50003)    RHOGAP (PS50238)   
    Domains : Interpro (EBI)Bcr-Abl_oncoprot_oligo    C2_dom    DH-domain    GDS_CDC24_CS    PH_like_dom    Pleckstrin_homology    Rho_GTPase_activation_prot    RhoGAP_dom   
    Related proteins : CluSTrP11274
    Domain families : Pfam (Sanger)Bcr-Abl_Oligo (PF09036)    C2 (PF00168)    PH (PF00169)    RhoGAP (PF00620)    RhoGEF (PF00621)   
    Domain families : Pfam (NCBI)pfam09036    pfam00168    pfam00169    pfam00620    pfam00621   
    Domain families : Smart (EMBL)C2 (SM00239)  PH (SM00233)  RhoGAP (SM00324)  RhoGEF (SM00325)  
    DMDM Disease mutations613
    Blocks (Seattle)P11274
    PDB (SRS)1K1F    2AIN   
    PDB (PDBSum)1K1F    2AIN   
    PDB (IMB)1K1F    2AIN   
    PDB (RSDB)1K1F    2AIN   
    Human Protein AtlasENSG00000186716
    Peptide AtlasP11274
    HPRD01044
    IPIIPI00004497   IPI00472302   IPI00896389   IPI00425739   IPI00916237   IPI00332355   IPI00742062   IPI00917533   IPI01019108   IPI00975613   IPI01014224   IPI01015189   IPI00964064   
    Protein Interaction databases
    DIP (DOE-UCLA)P11274
    IntAct (EBI)P11274
    FunCoupENSG00000186716
    BioGRIDBCR
    InParanoidP11274
    Interologous Interaction database P11274
    IntegromeDBBCR
    STRING (EMBL)BCR
    Ontologies - Pathways
    Ontology : AmiGOprotein serine/threonine kinase activity  protein tyrosine kinase activity  Rho guanyl-nucleotide exchange factor activity  GTPase activator activity  protein binding  ATP binding  phospholipid binding  cytosol  plasma membrane  protein phosphorylation  signal transduction  small GTPase mediated signal transduction  brain development  kinase activity  peptidyl-tyrosine phosphorylation  enzyme binding  actin cytoskeleton organization  negative regulation of cell migration  Rac GTPase activator activity  response to lipopolysaccharide  inner ear morphogenesis  negative regulation of neutrophil degranulation  protein autophosphorylation  platelet-derived growth factor receptor signaling pathway  negative regulation of inflammatory response  positive regulation of phagocytosis  neuromuscular process controlling balance  regulation of small GTPase mediated signal transduction  regulation of cell cycle  
    Ontology : EGO-EBIprotein serine/threonine kinase activity  protein tyrosine kinase activity  Rho guanyl-nucleotide exchange factor activity  GTPase activator activity  protein binding  ATP binding  phospholipid binding  cytosol  plasma membrane  protein phosphorylation  signal transduction  small GTPase mediated signal transduction  brain development  kinase activity  peptidyl-tyrosine phosphorylation  enzyme binding  actin cytoskeleton organization  negative regulation of cell migration  Rac GTPase activator activity  response to lipopolysaccharide  inner ear morphogenesis  negative regulation of neutrophil degranulation  protein autophosphorylation  platelet-derived growth factor receptor signaling pathway  negative regulation of inflammatory response  positive regulation of phagocytosis  neuromuscular process controlling balance  regulation of small GTPase mediated signal transduction  regulation of cell cycle  
    Pathways : BIOCARTAInhibition of Cellular Proliferation by Gleevec [Genes]    Integrin Signaling Pathway [Genes]   
    Pathways : KEGGPathways in cancer    Chronic myeloid leukemia   
    REACTOMEBCR
    Protein Interaction DatabaseBCR
    Wikipedia pathwaysBCR
    Gene fusion - rearrangments
    Rearrangement : COSMICBCR [22q11.23]  -  JAK2 [9p24.1]
    Rearrangement : TICdbABL1 [9q34.12]  -  BCR [22q11.23]
    Rearrangement : TICdbBCR [22q11.23]  -  ABL1 [9q34.12]
    Rearrangement : TICdbBCR [22q11.23]  -  BCR [22q11.23]
    Rearrangement : TICdbBCR [22q11.23]  -  BCR [22q11.23]
    Rearrangement : TICdbBCR [22q11.23]  -  FGFR1 [8p11.23]
    Rearrangement : TICdbBCR [22q11.23]  -  JAK2 [9p24.1]
    Rearrangement : TICdbBCR [22q11.23]  -  PDGFRA [4q12]
    Rearrangement : TICdbFGFR1 [8p11.23]  -  BCR [22q11.23]
    Rearrangement : TICdbJAK2 [9p24.1]  -  BCR [22q11.23]
    Rearrangement : TICdbPDGFRA [4q12]  -  BCR [22q11.23]
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)BCR
    SNP (GeneSNP Utah)BCR
    SNP : HGBaseBCR
    Genetic variants : HAPMAPBCR
    1000_GenomesBCR 
    ICGC programENSG00000186716 
    Cancer Gene: CensusBCR 
    Somatic Mutations in Cancer : COSMICBCR 
    CONAN: Copy Number AnalysisBCR 
    Mutations and Diseases : HGMDBCR
    OMIM151410    608232    613065   
    GENETestsBCR
    Disease Genetic AssociationBCR
    Huge Navigator BCR [HugePedia]  BCR [HugeCancerGEM]
    Genomic VariantsBCR  BCR [DGVbeta]
    Exome VariantBCR
    dbVarBCR
    ClinVarBCR
    snp3D : Map Gene to Disease613
    General knowledge
    Homologs : HomoloGeneBCR
    Homology/Alignments : Family Browser (UCSC)BCR
    Phylogenetic Trees/Animal Genes : TreeFamBCR
    Chemical/Protein Interactions : CTD613
    Chemical/Pharm GKB GenePA25321
    Clinical trialBCR
    Cancer Resource (Charite)ENSG00000186716
    Other databases
    Probes
    Litterature
    PubMed318 Pubmed reference(s) in Entrez
    CoreMineBCR
    iHOPBCR

    Bibliography

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    Hariharan IK, Adams JM.
    EMBO J. 1987 Jan;6(1):115-9.
    PMID 3107980
     
    Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia.
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    Cell. 1987 Oct 9;51(1):33-40.
    PMID 2820585
     
    Increased neutrophil respiratory burst in bcr-null mutants.
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    Cell. 1995 Mar 10;80(5):719-28.
    PMID 7889565
     
    The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein.
    Takeda N, Shibuya M, Maru Y.
    Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):203-7.
    PMID 9874796
     
    Bcr: a negative regulator of the Bcr-Abl oncoprotein.
    Wu Y, Ma G, Lu D, Lin F, Xu HJ, Liu J, Arlinghaus RB.
    Oncogene. 1999 Aug 5;18(31):4416-24.
    PMID 10442632
     
    The molecular biology of chronic myeloid leukemia.
    Deininger MW, Goldman JM, Melo JV.
    Blood. 2000 Nov 15;96(10):3343-56.
    PMID 11071626
     
    BCR-ABL down-regulates the DNA repair protein DNA-PKcs.
    Deutsch E, Dugray A, AbdulKarim B, Marangoni E, Maggiorella L, Vaganay S, M'Kacher R, Rasy SD, Eschwege F, Vainchenker W, Turhan AG, Bourhis J.
    Blood. 2001 Apr 1;97(7):2084-90.
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    The BCR gene and philadelphia chromosome-positive leukemogenesis.
    Laurent E, Talpaz M, Kantarjian H, Kurzrock R.
    Cancer Res. 2001 Mar 15;61(6):2343-55.
    PMID 11289094
     
    Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia.
    Arlinghaus RB.
    Oncogene. 2002 Dec 9;21(56):8560-7.
    PMID 12476302
     
    BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2.
    Perrotti D, Cesi V, Trotta R, Guerzoni C, Santilli G, Campbell K, Iervolino A, Condorelli F, Gambacorti-Passerini C, Caligiuri MA, Calabretta B.
    Nat Genet. 2002 Jan;30(1):48-58. Epub 2001 Dec 20.
    PMID 11753385
     
    Differential interaction and activation of Rho family GTPases by p210bcr-abl and p190bcr-abl.
    Harnois T, Constantin B, Rioux A, Grenioux E, Kitzis A, Bourmeyster N.
    Oncogene. 2003 Sep 25;22(41):6445-54.
    PMID 14508524
     
    The biology of CML blast crisis.
    Calabretta B, Perrotti D.
    Blood. 2004 Jun 1;103(11):4010-22. Epub 2004 Feb 24.
    PMID 14982876
     
    Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells.
    Krause DS, Lazarides K, von Andrian UH, Van Etten RA.
    Nat Med. 2006 Oct;12(10):1175-80. Epub 2006 Sep 24.
    PMID 16998483
     
    BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros.
    Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, White D, Hughes TP, Le Beau MM, Pui CH, Relling MV, Shurtleff SA, Downing JR.
    Nature. 2008 May 1;453(7191):110-4. Epub 2008 Apr 13.
    PMID 18408710
     
    Kinase domain mutants of Bcr enhance Bcr-Abl oncogenic effects.
    Perazzona B, Lin H, Sun T, Wang Y, Arlinghaus R.
    Oncogene. 2008 Apr 3;27(15):2208-14. Epub 2007 Oct 15.
    PMID 17934518
     
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    Contributor(s)

    Written10-1997Jean-Loup Huret
    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
    Updated04-2001Ali G Turhan
    Translational Research - Cell Therapy, Laboratory, Institut Gustave Roussy, INSERM U. 362, 1 - 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France
    Updated08-2008Ali G Turhan
    Pole de Biologie-Sante - 40 avenue du Recteur Pineau - 86022 Poitiers Cedex, France

    Citation

    This paper should be referenced as such :
    Huret JL . BCR (Breakpoint cluster region). Atlas Genet Cytogenet Oncol Haematol. October 1997 .
    Turhan AG . BCR (Breakpoint cluster region). Atlas Genet Cytogenet Oncol Haematol. April 2001 .
    Turhan AG . BCR (Breakpoint cluster region). Atlas Genet Cytogenet Oncol Haematol. August 2008 .
    URL : http://AtlasGeneticsOncology.org/Genes/BCR.html

    The various updated versions of this paper are referenced and archived by INIST as such :
    http://documents.irevues.inist.fr/bitstream/handle/2042/32042/10-1997-BCR.pdf   [ Bibliographic record ]
    http://documents.irevues.inist.fr/bitstream/2042/37746/1/04-2001-BCR.pdf   [ Bibliographic record ]
    http://documents.irevues.inist.fr/bitstream/2042/44509/1/08-2008-BCR.pdf   [ Bibliographic record ]

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Fri Apr 18 17:32:16 CEST 2014

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